Many biologically important functions are regulated by the transfer of a phosphate group. Often, the active or inactive form of a compound is determined by the presence or absence of a phosphate group bound to that compound. Accordingly, many biological enzymes are involved in regulating this phosphate group transfer. For example, kinase enzymes catalyze transfer of a phosphate group from a nucleoside triphosphate to a protein receptor. In contrast, phosphatase enzymes remove a phosphate group from a substrate by hydrolysis.
SHP-2 (src homology 2-containing protein tyrosine phosphatase) is a 68 kDa phosphatase protein and is also known as SHPTP2, Syp, PTP1D and PTP2C. Lu et al., Molecular Cell (2001) 8, 759. The enzyme is expressed in the cytoplasm of every tissue. SHP-2 is an important signaling enzyme, and the biological functions of SHP-2 have been extensively reviewed. Feng, Exp. Cell Res. (1999) 253, 45; Neel and Tonks, Curr. Opin. Cell Biol. (1997) 9, 193; Tonks, Adv. Pharmacol. (1996) 36, 91. The enzyme is activated through interactions with a variety of ligands including growth factors, cytokine receptor tyrosine kinases, and adhesion molecules and is most notably recognized as a positive regulator of cell proliferation. SHP-2 also plays an important function in immune signaling. Huyer and Alexander, Curr. Biol. (1999) 9, R129; Cohen et al., Cell (1995) 80, 237. The SHP-2 enzyme is required for activation of the Ras-MAP kinase cascade, although its precise role in the pathway is unclear. Van Vactor et al., Curr. Opin. Genet. Dev. (1998) 8, 112. SHP-2 has recently been identified as an intracellular target of Helicobacter pylori. Higashi et al., Science (2002) 295, 683. Due to the critical role SHP-2 plays in various biological pathways, development of inhibitors against the enzyme would provide useful treatments for cancer and other autoimmune diseases.
Development of new chemical entities that modulate phosphatase enzymes such as SHP-2 would be an important advance and could lead to the development of novel treatments for diseases in which phosphatase enzymes play a critical role. The development of phosphatase modulators is an active area of research and has been extensively reviewed. Ripka, Annual Rev. Med. Chem. (2000) 35, Chapter 21 and references cited therein.
The majority of compounds investigated to date as potential phosphatase inhibitors can be divided into two general classes. The most common phosphatase inhibitors incorporate one or two carboxylate groups to mimic the two formal negative charges present on phosphate at physiological pH. Another common class of phosphatase inhibitors incorporates the mono- or diflouro phosphinate moiety as a non-hydrolyzable phosphate group mimic.
More recent work has focused on the development of new heterocyclic groups that can mimic a phosphate moiety, i.e. the development of phosphate isosteres. A successful phosphate isostere will ideally be both nonhydrolyzable and bioavailable. Successful phosphate mimicry will also depend on the shape and ionization state of the mimic. Examples of new heterocyclic groups designed to mimic a phosphate moiety include tetronic acid derivatives investigated against Cdc25b, Sodeoka et al., J. Med. Chem. (2001) 44(20), 3216, and the azoledinedione class of inhibitors that have been investigated against protein tyrosine phosphatase 1B (PTB1B). Malamas et al., J. Med. Chem. (2000) 43, 995. However, the efficacy of these mimics is still being investigated.
Although 2-alkyl sulfhydantoins have been reported as serine protease inhibitors, Groutas et al., Biochemistry (1997) 36, 4739; Hlasta et al., J. Med. Chem. (1995) 38, 4687, they have never been recognized as phosphate mimics.
There is still a great need to develop potent modulators of phosphatase enzymes and other enzymes that are involved in regulating the transfer of a phosphate group. There is also a need to develop new chemical entities useful as phosphate isosteres.